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Polysubstituted triazole formate derivative and application thereof

An unsubstituted and deuterated technology, applied in the field of multi-substituted triazole carboxylate derivatives, can solve the problem of not being found

Active Publication Date: 2020-01-10
CHENGDU MFS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And have successively found etomidate analogues such as Dimethylmethoxycarbonyl metomidate (DMMM) and Cyclopropyl methoxycarbonyl metomidate (CPMM), but have not yet found that both retained the unique advantages of etomidate (such as high efficiency, safety), and eliminated its adverse effects Compounds with inhibitory effects on adrenocortical function

Method used

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  • Polysubstituted triazole formate derivative and application thereof
  • Polysubstituted triazole formate derivative and application thereof
  • Polysubstituted triazole formate derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0230] Embodiment 1 Preparation of compound 1 and compound 2 of the present invention

[0231]

[0232] 1. Preparation of (R)-(1-Azidoethyl)benzene(1-2)

[0233]

[0234] In an ice-water bath at 0°C, 1-1 (20g, 164mmol) and PPh 3 (85.9g, 328mmol) was dissolved in THF (300mL), then a THF (50mL) solution of DEAD (57.1g, 328mmol) was added dropwise, added dropwise to the system at a rate of 10mmol / min, and then DPPA (54.1g, 197mmol ) was added dropwise to the system at a rate of 6 mmol / min, and after the dropwise addition was completed, it was slowly raised to room temperature and stirred overnight. After the completion of the reaction was monitored by TLC, saturated saline (150mL) was added to the reaction system, extracted with n-hexane (3×50mL), separated into three layers, the uppermost layer was collected, and the uppermost organic phase was combined with saturated saline (50mL ), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pr...

Embodiment 2

[0242] Embodiment 2 The preparation of compound 3~compound 32 of the present invention

[0243]

[0244] 1. Preparation of Compound A

[0245]

[0246] At room temperature, the LiOH.H 2 O (220mg, 5.24mmol) was added to compound 1 (643mg, 2.62mmol) in MeOH / THF / H at one time 2 O (3mL, 1 / 1 / 1) solution, stirred overnight at room temperature. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated, and water (10 mL) was added to the system. After adjusting the pH to 4-5 with 1N hydrochloric acid, it was extracted with dichloromethane (3×15 mL), and the combined organic phases were washed with anhydrous sodium sulfate Drying, suction filtration, and concentration under reduced pressure gave white solid Compound A (545 mg, yield 96%). ESI[M+H] + =218.2

[0247] 1 H NMR (400MHz, CDCl 3 )δ8.25(s,1H),7.38–7.30(m,5H),6.58–6.52(m,1H),2.10(d,J=7.0Hz,3H).

[0248] 2. Preparation of Target Compound 3~Compound 32

[0249]

[0250] Prep...

Embodiment 3

[0311] Embodiment 3 Preparation of compound 33 and compound 34 of the present invention

[0312]

[0313] 1-2 (5.1 g, 34.7 mmol) and 33-1 (8.1 g, 69.8 mmol) were dissolved in toluene (50 mL) at room temperature, and stirred at reflux for 14 hours. After the reaction was monitored by TLC, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=1 / 10~1 / 1), TLC (ethyl acetate / petroleum ether (v / v)=1 / 5) monitoring, and collected fractions with Rf=0.5-0.6 to obtain target compound 33 (890 mg, yield 10%) and target compound 34 (1.2 g, yield 13%).

[0314] Compound 33: ESI[M+H] + =264.3

[0315] 1 H NMR (400MHz, CDCl 3 )δ7.42–7.21(m,5H),6.57–6.53(m,1H),4.45–4.26(m,2H),2.02(d,J=7.1Hz,3H),1.37(t,J=7.1Hz ,3H).

[0316] Compound 34: ESI[M+H] + =264.3

[0317] 1 H NMR (400MHz, CDCl 3 )δ7.41–7.23(m,5H),6.54–6.51(m,1H),4.41–4.21(m,2H),2.03(d,J=7.1Hz,3H),1.33(t,J=7.1Hz ,3H).

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Abstract

The invention discloses a compound shown as formula I in the specification, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative thereof. Belonging to the field of pharmaceutical chemistry, the compound is a polysubstituted triazole formate derivative with a novel structure. The invention also discloses application of thepolysubstituted triazole formate derivative in preparation of drugs with sedative, hypnotic and / or anesthetic effects, and application in preparation of drugs capable of controlling status epilepticus. The compound has good inhibition effect on the central nervous system, and provides a new choice for clinical screening and / or preparation of drugs with sedative, hypnotic and / or anesthetic effectsand status epilepticus controlling function.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of polysubstituted triazole carboxylate derivatives with novel structures, and the use of such compounds in the preparation of drugs with sedative, hypnotic and / or general anesthesia and drugs capable of controlling status epilepticus application in medicine. Background technique [0002] An imidazole derivative etomidate, the chemical name is R-(+)-1-(1-phenylethyl)-1-hydro-imidazole-5-ethyl carboxylate, which is a hypnotic intravenous general anesthetic , with a wide range of safety, it was once one of the commonly used drugs for anesthesia induction. The clinical application of imidazole derivatives has a history of 30 years (Br J Anaesth.1976; 48 (3): 213-6. PubMed: 1259887; Arch Int Pharmacodyn Ther.1975; 214 (1): 92-132. PubMed : 1156027; AcadEmerg Med. 2006; 13(4):378-83. PubMed: 16531603). Etomidate is a non-barbiturate intravenous sedative drug, i...

Claims

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Application Information

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IPC IPC(8): C07D249/04C07D405/12C07D409/12A61K31/4192A61P25/20A61P23/00A61P25/08
CPCC07D249/04C07D405/12C07D409/12A61P25/20A61P23/00A61P25/08C07B2200/07
Inventor 马海军王昌华解振彪
Owner CHENGDU MFS PHARMA CO LTD
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